Reduced Rap1 Signaling Contributes to Prostate Cancer Progression

• Published in: The FASEB journal 2007-04, Vol.21 (5), p.A78-A78
• Main Authors: Henderson, Veronica M, Ali‐Seyed, Mohamed, Genetta, Thomas L, Kitayama, Hitoshi, Csete, Marie E, Moreno, Carlos S
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.21.5.A78

Rap1 is a small G‐protein that has high homology to the Ras oncogene and is a regulator of E‐cadherin and integrin mediated cell adhesion. Our expression profiling of 57 prostate cancer tissue samples indicates that RAP1A and RAP1GAP were among the 36 genes most strongly correlated with cancer progression as measured by Gleason score. Rap1A expression decreases as prostate cancers progress, while expression of RAP1GAP increases. We have confirmed the mRNA changes by QRT‐PCR, and observed by immunohistochemistry that RAP1GAP protein is more abundant in localized PCa than in benign hyperplasia. Furthermore, we found that inhibition of Rap1 signaling with a dominant negative mutant enhanced prostate cancer cell migration, while activation of Rap1 with a consitutively active mutant inhibited migration. In addition, siRNA knockdown of RAP1GAP also inhibited migration of prostate cancer cells. We also found that RAP1A and RAP1B mRNA and protein levels are reduced by hypoxic conditions. The promoters of both genes are occupied by two zinc‐finger transcription factors under normoxia, but not under hypoxia. These data lead to a model in which hypoxia results in reduced occupancy of the RAP1A and RAP1B genes by the ZEB transcription factors, reduced Rap1 signaling, reduced cell‐cell adhesion, and increased migratory, invasive, and metastatic potential.